Synthesis ofβ3-Peptides and Mixedα/β3-Peptides by Thioligation

Abstract

Five β-peptide thioesters (1–5, containing 3, 4, 10 residues) were prepared by manual solid-phase synthesis and purified by reverse-phase preparative HPLC. A β-undecapeptide (6) and an α-undecapeptide (7) with N-terminal β3-HCys and Cys residues were prepared by manual and machine synthesis, respectively. Coupling of the thioesters with the cysteine derivatives in the presence of PhSH (Scheme and Fig. 1) in aqueous solution occurred smoothly and quantitatively. Pentadeca- and heneicosapeptides (8–10) were isolated, after preparative RP-HPLC purification, in yields of up to 60%. Thus, the so-called native chemical ligation works well with β-peptides, producing larger β3- and α/β3-mixed peptides. Compounds 1–10 were characterized by high-resolution mass spectrometry (HR-MS) and by CD spectroscopy, including temperature and concentration dependence. β-Peptide 9 with 21 residues shows an intense negative Cotton effect near 210 nm but no zero-crossing above 190 nm, (Figs. 2–4), which is characteristic of β-peptidic 314-helical structures. Comparison of the CD spectra of the mixed α/β-pentadecapeptide (10) and a helical α-peptide (Fig. 5) indicate the presence of an α-peptidic 3.613 helix.